This invention relates to aminotriazole analogues that are antagonists of P2X7 receptors, and to the use of such compounds for treating conditions related to P2X7 receptor activation.
P2X receptors are ionotropic receptors activated by ATP. The importance of P2X receptors in nociception is underscored by the variety of pain states in which this endogenous ligand can be released. Of the seven P2X receptors, the P2X7 is distinguished by its ability to form a large pore upon prolonged or repeated agonist stimulation. It is partially activated by saturating concentrations of ATP, whereas it is fully activated by the synthetic ATP analog benzoylbenzoic ATP (BzATP) (Bianchi et al., Eur. J. Pharmacol. Vol. 376, pages 127-138, 1999). The P2X7 receptor is expressed by presynaptic terminals in the central and peripheral nervous systems, antigen-presenting cells including macrophages, human epidermal Langerhans' cells, microglial cells and a number of tumor cell lines of varying origin (Jacobson K A, et al. “Adenosine and Adenine Nucleotides: From Molecular Biology to Integrative Physiology”. L. Belardinelli and A. Pelleg (eds.), Kluwer, Boston, pages 149-166, 1995).
Recent studies demonstrated the participation of P2X7 receptors in the modulation of electrical stimulation and ATP-evoked GABA and glutamate release from mouse hippocampal slices (Papp et al., Neuropharmacolozy and Neurotoxicology Vol. 15, pages 2387-2391, 2004)). In the central nervous system, the P2X7 receptor is predominately expressed by microglia, the resident macrophages of the brain. On glial cells, the P2X7 receptor has been shown to mediate release of glutamate (Anderson C. et al. Drug Dev. Res. Vol. 50. page 92, 2000). Upregulation of the P2X7 receptor, most likely on activated microglia, was reported in association with ischemic damage and necrosis induced by occlusion of middle cerebral artery in rat brain (Collo G. et al. Neuropharmacology, Vol. 36, pages 1277-1283, 1997). Recent studies indicate a role of the P2X7 receptor in the generation of superoxide in microglia, and upregulation of P2X7 receptors around β-amyloid plaques in a transgenic mouse model for Alzheimer's disease (Parvathenani et al., J. Biol. Chemistry, Vol. 278, pages 13300-13317, 2003) and in multiple sclerosis lesions from autopsy brain sections (Narcisse et al., Glia. Vol. 49, pages 245-258 (2005).
Activation of the P2X7 receptor on cells of the immune system (macrophages, mast cells and lymphocytes) leads to release of interleukin-1β (IL-1β), giant cell formation, degranulation, and L-selectin shedding. ATP has been shown to increase local release and processing of IL-1β following lipopolysaccharide S (LPS) intraperitoneal injections in rats through a P2X7 receptor mediated mechanism (Griffiths et al., J. Immunology Vol. 154, pages 2821-2828 (1995); Solle et al., J. Biol. Chemistry. Vol. 276, pages 125-132, (2001)).
Oxidized ATP (oATP), a nonselective and irreversible P2X7 antagonist, was recently reported to possess peripherally mediated antinociceptive properties in inflamed rats (Dell'Antonio et al. Neuroscience Lett., Vol. 327, pages 87-90, 2002). Activation of P2X7 receptors localized on presynaptic terminals in the central and peripheral nervous systems (Deuchars et al J. Neuroscience, Vol. 21, pages 7143-7152, 2001) induced release of the excitatory amino acid neurotransmitter glutamate.
Studies from mice lacking the P2X7 receptor resulted in absence of inflammatory and neuropathic hypersensitivity to mechanical and thermal stimuli, indicating a link between a P2X7 purinoceptor gene and inflammatory and neuropathic pain (Chessell et al., Pain, Vol 114, pages 386-396 (2005)).
Antagonists to the P2X7 receptor significantly improved functional recovery and decreased cell death in spinal cord injury (SCI) animal models. Rats with SCI were administered P2X7 receptor irreversible antagonists oATP and PPADS with a resulting decrease of histological injury and improved recovery of motor function after the lesions (Wang et al., Nature Medicine Vol. 10, pages B21-B27, 2004).
Taken together, these findings indicate that compounds acting at the P2X7 receptor may have utility in the treatment of pain, including neuropathic pain, inflammatory processes, and degenerative conditions associated with disease states such as rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease, airways hyper-responsiveness, septic shock, glomerulonephritis, irritable bowel disease, Crohn's disease, ulcerative colitis, atherosclerosis, growth and metastases of malignant cells, myoblastic leukemia, diabetes, Alzheimer's disease, multiple sclerosis, meningitis, osteoporosis, bum injury, ischemic heart disease, stroke and varicose veins.
In view of the above facts, there is a need for selective P2X7 antagonist that can be efficiently used in preventing, treating, or ameliorating states as neuropathic pain, chronic inflammatory pain, inflammation and neurodegenerative conditions associated with several progressive CNS disorders, including, but not limited to, Alzheimer's disease, Parkinson's disease, depression, amyotrophic lateral sclerosis, Huntington's disease, dementia with Lewy bodies, multiple sclerosis as well as diminished CNS function resulting from traumatic brain injury.